Laboratory animals to which heterologous cells including human cells are engrafted are very important for analysis of onset mechanisms of various diseases and drug developments for the treatments or preventions thereof, and development of animals as receptors therefor is one of major themes in laboratory animal sciences. In particular, in recent years, treatments etc. (known as regenerative medicine) in which tissues or cells differentiated from stem cells are transplanted have received world-wide attention, and therefore these animals are of increasing importance.
The inventors of the present invention have continued to develop and improve these laboratory animals. In particular, they made improvements or the like on a nude mouse or a SCID mouse, and they have already filed a patent application (Japanese Patent Application Laying-Open (kokai) No. 9-94040) concerning an immunodeficient mouse etc. produced for this purpose. Above all, an NOD/Shi-scid mouse and an NOD/LtSz-scid mouse which exhibit multifunctional immunodeficiency (functional deficiency of T cells and B cells, decline of macrophage function, reduction of complement activity, reduction of natural killer (NK) activity etc.) are the most noteworthy as laboratory animals suitable for engraftment of heterologous cells. Since it became clear that they could be used for various types of research including stem cell differentiation and proliferation, the range of applications in which they are used has increased to the present level.
However, human cells are engrafted to the NOD/Shi-scid mouse at a high ratio, but it is recognized that the engraftment capacity is substantially varied.
In order to enhance the engraftment capacity of the NOD/Shi-scid mouse, it has already been revealed that reduction of NK activity in the mouse by administering anti IL-2Rβ chain antibodies (TMβ1), anti-asialo-GM1 antibodies or the like is important. (Koyanagi, Y. et al., 1997. “Primary human immunodeficiency virus type 1 viremia and central nervous system invasion in a novel hu-PBL-immunodeficient mouse strain.” J Virol 71:2417; Koyanagi, Y. et al., 1997. “High levels of viremia in hu-PBL-NOD-scid mice with HIV-1 infection.” Leukemia 11 Suppl. 3:109; Yoshino H, et al., 2000. “Natural killer cell depletion by anti-asialo GM1 antiserum treatment enhances human hematopoietic stem cell engraftment in NOD/Shi-scid mice.” Bone Marrow Transplant 26:1211-6. However, these antibodies are very expensive, and it is recognized that their efficacies vary between individuals. Further, when anti-asialo GM1 antibodies are used, the administration thereof should be conducted with the frequency of every eleventh day during the experiment period, and thus a degree of complexity is attached.
Therefore, Dr. Shultz, L. D. et al. of The Jackson Laboratory in the United States produced an NOD/LtSz-scid, β2m null (β2m (null)NOD/SCID) mouse (Kollet O, Peled A, Byk T et al., beta2 microglobulin-deficient (β2m(null))NOD/SCID mice are excellent recipients for studying human stem cell function. Blood 2000; 95(10):3102-5) by crossing an NOD/LtSz-scid mouse having high engraftment capacity of human cells with a β2m KO mouse from which NK activity has been depleted.
With respect to the NOD/LtSz-scid, β2m null mouse, T cells, B cells and natural killer (NK) cells are depleted, and the function of macrophages and complements is reduced. However, other cells (e.g. dendritic cells) and factors (e.g. IFNγ) are also involved in the rejection of transplanted heterologous cells or tissues.
Accordingly, a mouse which, compared to the NOD/LtSz-scid, β2m null mouse, has no variation in heterologous cell engraftment capacity, requires no antibodies, and has excellent heterologous cell engraftment is desirable.